Separatory devices useful in biomedical applications such as kidney dialysis, heomodialysis, hemoultrafiltration, blood oxygenation and the like are well known. Such devices generally consist of at least one separatory membrane or element, disposed in a housing or casing having an inlet and an outlet means. The separatory membrane may take the form of a hollow fiber, film, screen, and the like and is chosen for its ability to perform the intended biomedical function.
While various methods of manufacture have been described, certain of such methods employ potting or sealing resins to secure the separatory membranes in the housing and prevent the mixing of fluids which pass on either side of the membrane when necessary.
The choice of suitable potting resins is limited by the fact that they must be non-toxic during operation of the separatory device. As used herein the terms non-toxic is intended to characterize a potting resin which when incorporated into a separatory device does not contain toxic components which are releasable into the fluids which pass through the separatory device as determined by the Hemolysis test described herein. While non-toxic potting resins are known they possess certain deficiencies which can best be illustrated with reference to separatory devices which employ hollow fibers.
Such devices typically consist of a plurality of permeable hollow fibers whose terminal portions are potted in a sealing collar and extend therethrough thereby providing liquid access to the interior of the fibers.
The separatory elements are then typically sealed within a casing to form a separatory cell having one or more liquid ports which allow for the passage of one fluid, such as blood, through the fibers and another fluid around the fibers without mixing the two fluids. The separatory element may have two sealing collars or a single sealing collar in which latter case the fibers are doubled back so that all the ends terminate together. The general configuration of the separatory element and separatory cell is similar to a tube-and-shell heat exchanger.
Patents representative of the art of hollow fiber separatory devices include U.S. Pat. Nos. 2,972,349, 3,228,876, 3,228,877, 3,422,008, 3,423,491, 3,339,341, 3,503,515, 3,551,331 and the like the disclosures of which are herein incorporated by reference.
The sealing collar is typically derived from a resin which is capable of encapsulating the fibers to provide a seal which prevents the fluid inside the hollow fibers from mixing with the fluid outside the fibers.
A preferred class of resins useful for preparing the sealing collars are flexible polyurethane forming systems as illustrated by U.S. Pat. Nos. 3,962,094 and 4,031,012 the disclosures of which are herein incorporated by reference. Centrifugal casting, as illustrated by U.S. Pat. No. 3,492,698, the disclosure of which is herein incorporated by reference, is a representative method employed for preparing sealing collars. In accordance with such a technique, a holding device containing a bundle of fibers arranged in a parallel configuration is placed into a centrifugal-like device which incorporates a potting-material reservoir with tubes connecting it to end-molds. An appropriate resin is placed into the potting reservoir maintained at an appropriate temperature. The entire assembly is then rotated to force the resin down the connecting tubes by the centrifugal force. The resin thereby flows around and among the fibers in the end-molds. The rotation is continued until the resin gels. When polyurethanes are employed as the resin, typical residence time in the centrifuge can vary from about 1 to about 8 hours at room temperature. When rotation is completed the resin impregnated fiber bundle is removed and post cured. The end molds are then removed and the fiber ends are opened by cutting through the resin collar perpendicular to the fiber bundle.
Other sealing collar forming techniques rely on the force of gravity to force the resin into a mold containing the ends of the hollow fibers. The resin is allowed to gel and then is post cured.
Regardless of the particular method employed for preparing the sealing collar the polyurethanes typically employed therein exhibit extended gel and demold, i.e., post cure, times.
The same polyurethane resins that are employed in preparing hollow fiber separatory devices are used to perform similar functions in other separatory devices wherein a separatory membrane is provided in a configuration different from that of hollow fibers. Thus, while the configuration of the separatory membranes differ in commercially available separatory devices, the problems of extended cure times are common to all.
Catalysts are known that are specific for increasing the hydroxyl-isocyanate reaction rate such as aliphatic and cycloaliphatic tertiary amines, and soluble metal compounds, particularly organotin compounds.
The selection of a suitable catalyst for use in a polyurethane system intended as a potting resin for a biomedical device is complicated by the requirement that the resin system be non-toxic. Thus, the aliphatic and cycloaliphatic tertiary amines are unsuitable because of their toxicity. Although tin-octoate has been used as a catalyst and is non-toxic it is hydrolytically unstable and must be added to the polyol on site rather than during packaging of the polyol. Ferric acetyl acetonate can also be used as a catalyst but it is toxic at levels of about 0.1% by weight and higher and imparts a dark red color to the polyurethane.
The hydroxyl-isocyanate reaction rate of polyurethane forming systems is also known to be slightly increased by strong acids as illustrated by J. Saunders and K. Frisch, Polyurethanes, Chemistry and Technology at 211-15 (1962).
However, acids in general are very toxic when introduced into the blood stream and their residual presence in potting resins used in preparing biomedical devices has heretofore been avoided because of the risk that they will be absorbed into the fluids passing through the device.
The search has therefore continued for a polyurethane composition, and separatory devices employing the same which are non-toxic, and which can be prepared in a more cost efficient manner than has heretofore been possible. The present invention is a result of this search.